免疫检查点抑制剂诱导的心肌炎伴肌炎和/或重症肌无力重叠综合征：病例系列

文献信息

中文摘要

免疫检查点抑制剂（ICIs）可导致免疫相关不良事件，包括心肌炎伴肌炎和/或重症肌无力重叠综合征（IM3OS）。该综合征带来显著的管理挑战，且死亡率高。由于数据有限，其临床特征和最佳治疗策略仍知之甚少。本研究旨在阐明这些方面并分享临床管理经验。回顾性分析了6例IM3OS患者，收集人口学、临床、实验室、电生理、治疗和结局数据。此外，还回顾了相关文献以对研究结果进行背景化。6例患者均为男性，中位年龄70.5岁（范围63-83岁），在ICI启动后中位30.5天出现症状。常见症状包括波动性上睑下垂、颈部无力、疲劳、肌痛、复视、吞咽困难、构音障碍和肢体无力。6例患者中，3例需要通气支持。所有患者均观察到肌酸激酶（CK）和心肌肌钙蛋白I（cTnI）升高，治疗后CK和cTnI水平迅速下降。心肌肌钙蛋白T水平持续升高3个月。2例患者出现肌强直放电和抖动增加。治疗包括皮质类固醇、静脉注射免疫球蛋白（IVIG）、血浆置换和利妥昔单抗。4例患者中有2例因严重心脏不良反应停用吡啶斯的明。尽管进行了干预，仍有2例患者死亡，1例卧床，仅3例预后良好。总之，IM3OS病死率高，强调对接受ICI治疗且出现神经肌肉症状的患者需要及时干预。血清cTnI是可靠的心脏损伤标志物，推荐早期使用IVIG、血浆置换和大剂量甲泼尼龙治疗。在IM3OS患者中应谨慎使用吡啶斯的明，尤其是在存在缓慢性心律失常性ICI相关心肌炎时。鉴于IM3OS相关的高死亡率和致残率，新型生物靶向治疗如依库珠单抗和艾加莫德可能减少致命结局。

英文摘要

Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events, including myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS). This syndrome poses notable management challenges and has high mortality rates. Due to limited data, its clinical features and optimal treatment strategies remain poorly understood. The present study aims to clarify these aspects and share clinical management experiences. A total of 6 patients with IM3OS were retrospectively analyzed, collecting demographic, clinical, laboratory, electrophysiological, therapeutic and outcome data. Additionally, the relevant literature was reviewed to contextualize the findings. The 6 patients, all male, with a median age of 70.5 years (range, 63-83 years), developed symptoms a median of 30.5 days post-ICI initiation. Common symptoms included fluctuating ptosis, neck weakness, fatigue, myalgia, diplopia, dysphagia, dysarthria and limb weakness. Of the 6 patients, 3 required ventilation support. Elevated creatine kinase (CK) and cardiac troponin I (cTnI) were observed in all patients, with CK and cTnI levels decreasing rapidly post-treatment. Cardiac troponin T levels remained elevated for 3 months. Myotonic discharge and increased jitter were noted in 2 patients. Treatments included corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis and rituximab. Pyridostigmine was discontinued in 2 out of 4 patients due to severe cardiac adverse effects. Despite interventions, 2 patients died and 1 was bedridden, with only 3 showing favorable outcomes. In conclusion, IM3OS has a high fatality rate, highlighting the need for prompt intervention in ICI-treated patients with neuromuscular symptoms. Serum cTnI is a reliable cardiac injury marker, and early treatment with IVIG, plasmapheresis and high-dose methylprednisolone is recommended. Pyridostigmine should be administered with caution in patients with IM3OS, particularly in the presence of bradyarrhythmic ICI-related myocarditis. Given the high mortality and disability rates associated with IM3OS, novel biological targeted therapies such as eculizumab and efgartigimod may reduce fatal outcomes.